Conventional signalling by the group I metabotropic glutamate receptors, mGluR1 and mGluR5, occurs through G-protein coupling, but evidence suggests they might also utilize other, non-canonical effector pathways. Here we test whether group I mGluRs require β-arrestin signalling during specific forms of plasticity at hippocampal excitatory synapses. We find that genetic ablation of β-arrestin2, but not β-arrestin1, results in deficits in plasticity mediated by mGlu1 receptors in CA3 pyramidal neurons and by mGlu5 receptors in CA1 pyramidal neurons. Pharmacological studies additionally support roles for Src kinases and MAPK/ERK downstream of β-arrestin2 in CA3 neurons. mGluR1 modulation of intrinsic conductances is otherwise preserved in β-arrestin2−/− mice with the exception of a rebound depolarization, and non-mGluR-mediated long-term potentiation is unaltered. These results reveal a signalling pathway engaged by group I mGluRs to effect changes in synaptic and cell intrinsic physiology dependent upon β-arrestin rather than G proteins. Pharmacological manipulation of mGluRs with effector-biased ligands could lead to novel therapies to treat neurological disease.
IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.
Background: Kalirin-7 is a neuronal Rac1-GEF that regulates spine morphology. X11␣ is a PDZ scaffolding protein.Results: X11␣ binds kalirin-7 and modulates its localization to Golgi outposts, GEF activity, and spine morphology. Conclusion: X11␣ is a novel regulator of small GTPase signaling by recruitment to Golgi outposts. Significance: We identify a novel mechanism for regulation of neuronal GEF localization and function.
Olfactory cues that indicate predation risk elicit a number of defensive behaviors in fishes, but whether they are sufficient to also induce morphological defenses has received little attention. Cichlids are characterized by a high level of morphological plasticity during development, and the few species that have been tested do exhibit defensive behaviors when exposed to alarm cues released from the damaged skin of conspecifics. We utilized young juvenile Nicaragua cichlids Hypsophrys nicaraguensis to test if the perception of predation risk from alarm cue (conspecific skin extract) alone induces an increased relative body depth which is a defense against gape-limited predators. After two weeks of exposure, siblings that were exposed to conspecific alarm cue increased their relative body depth nearly double the amount of those exposed to distilled water (control) and zebrafish Danio rerio alarm cue. We repeated our measurements over the last two weeks (12 and 14) of cue exposure when the fish were late-stage juveniles to test if the rate of increase was sustained; there were no differences in final dimensions between the three treatments. Our results show that 1) the Nicaragua cichlid has an innate response to conspecific alarm cue which is not a generalized response to an injured fish, and 2) this innate recognition ultimately results in developing a deeper body at a stage of the life history where predation risk is high.
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